The long-term objective of this project is to test the hypotheses, which were proposed by us in previous years and are now gaining acceptance, that the sensitivity of target organs is a dynamic phenomenon controlled by inherent feedback mechanisms; that experimental manipulation of this sensitivity provides a new avenue for studying individual components of complex systems like the eye, in which several target organs have the same pharmacological characteristics; that such alterations in target organ sensitivity may affect the efficacy of drugs; and that the cause of some disorders involves the failure of such control mechanisms which, once identified, can be corrected by pharmacological means. Our specific aims for the next five-years will be to elucidate the nature and specificity of pharmacologically- (DFP, pilocarpine, oxotremorine) and physiologically-induced (stimulus deprivation or overstimulation) sensitivity changes, using intraocular muscles as primary model systems. We will develop techniques to induce subsensitivity in the iris sphincter without affecting the sensitivity of the ciliary muscles, to induce specific subsensitivity in each subcomponent of the muscarinic system, and will use the techniques of selective sensitivity alterations as one means of analyzing the complexity of the muscarinic system. We will further test the hypothesis that such changes in sensitivity are associated with changes in the concentration of (different subpopulations of) muscarinic receptors. We will also study the effects of altered iris sphincter and ciliary muscle sensitivity on the normal functions of these organs using pupillographic and ultrasonic techniques, respectively. Elucidation of the mechanism of the control of target organ sensitivity is of great general significance with regard to virtually all areas of biomedical science and especially with regard to the eye, where autonomic agents are used chronically for the treatment of glaucoma and accomodative esotropia. Experiments aimed at identifying the endogenous factors responsible for episodes of sustained miosis in cholinergically subsensitive rhesus eyes will also be undertaken. Such studies may explain the cause of sustained miosis in the eyes of cholinesterase inhibitor-treated patients, which should be subsensitive to ACh, and reveal some, as yet unknown, basic aspects of cholinergic mechanisms.